ETIOLOGY

Influenza viruses are negative-sense, single-stranded, segmented RNA viruses that belong to the family Orthomyxoviridae. Influenza viruses types B and C are mainly human pathogens and are seen only rarely in animals (for example, in pigs and seals).⁷ Influenza A viruses, however, act as pathogens in many mammalian species (pigs, horses, ferrets, minks, aquatic mammals), including human beings, as well as in birds.⁸ Influenza A viruses are classified into distinct subtypes according to different hemagglutinin and neuraminidase glycoprotein molecules expressed on the surface. These viruses can either lead to subclinical infection or can cause serious systemic disease, depending on their pathogenicity. Among the subtypes H5 and H7, highly pathogenic variants may develop by mutation out of low-pathogenic avian influenza viruses.⁹

Older studies have shown that cats are somewhat susceptible to infection by several influenza viruses. Cats could be infected with human (H3N2), avian (H7N3), and seal (H7N7) isolates. After infection, they developed antibodies, sometimes even shed virus, but never became sick.¹⁰ In one kitten living in close contact to a human being who suffered from influenza, virus was isolated from the kitten and antibodies were detected; however, no clinical signs were observed in the kitten.¹¹ In addition, presence of antibodies against human influenza viruses was demonstrated in field cats in Japan but without correlation to clinical signs.¹²

However, since the recent discovery of highly pathogenic avian influenza virus H5N1 (HPAIV H5N1), it has become obvious that cats infected with this influenza virus also can become sick and die from the infection. Highly pathogenic avian influenza virus (HPAIV) subtype H5N1 was first detected in 1996 in domestic geese in China.^13,14 After several reassortment events, this avian virus not only caused serious disease in poultry but also crossed the species barrier to infect people in Hong Kong in 1997.^14–16 During the subsequent years, different H5N1 genotypes emerged after a series of genetic changes, leading to fatal outbreaks in Asia in poultry in 2003 and 2004.^14,17 Since then, HPAIV H5N1 has spread into many countries worldwide, resulting in high mortality in poultry and fatal infections in mammalian species including human beings. Mammalian species susceptible to HPAIV H5N1 include human beings,^18,19 ferrets,^20,21 dogs,^22,23 mice,²⁴ stone martens,²⁵ pigs,²⁶ cynomolgus monkeys,^27,28 civets,²⁹ domestic cats,^4,30 tigers, and leopards.¹

In felids, several outbreaks of infection with HPAIV H5N1 have been reported to date. The first outbreak was seen in 2003, when two tigers and two leopards suffering from high fever and respiratory distress died in a zoo in Suphanburi, Thailand.¹ Shortly after, a clouded leopard died in a zoo in Chonburi, Thailand, from infection with influenza A H5N1. One month later, a tiger at the same zoo was found to be infected but recovered from the disease.³¹ During an outbreak in a tiger zoo in Sriracha, Thailand, a total of 147 tigers died or were euthanized.⁵ First evidence that domestic cats are at risk was in 2004, when three domestic cats from a household in Thailand, in which 14 cats had died, were tested positive for influenza A H5N1.³¹ The virus also was detected in a domestic cat in Thailand who had died showing high fever, dyspnea, convulsions, and ataxia.² Experimental infection using an H5N1 virus (isolated from a fatal human case) confirmed that cats can develop severe clinical signs after intratracheal inoculation or after feeding on infected chicken.⁴ The first cases of HPAIV H5N1 infection in domestic cats in Europe were detected during the outbreak of avian influenza on the German Isle of Ruegen in February 2006, during which three free-roaming cats found dead were harboring the virus.⁶ At approximately the same time, three cats who did not show clinical signs tested positive by polymerase chain reaction (PCR) for influenza A H5N1 in an animal shelter in Graz, Austria, after an infected swan had been brought to the shelter.³

EPIDEMIOLOGY

Incidence of avian influenza in felids is associated with the occurrence of infections in poultry or wild birds in the surrounding area.^1,3,6 Phylogenetic analyses have shown that virus isolates from cats and tigers are highly similar to the virus circulating in poultry at the same time and that the viruses found in felids are of avian origin, indicating that no genetic reassortment with mammalian influenza viruses has occurred. Several point mutations have been identified that are associated with higher virulence in mammals; however, none of them seems to be essential for an infection in felids.^1,32–34

Within the H5N1 subtype, at least two genetically and antigenically distinct lineages (clades 1 and 2) exist in nonoverlapping geographic distributions in Asia. Clade 1 was isolated mainly in Vietnam and Thailand, whereas clade 2 was found mainly in China and Indonesia. From there, the “Qinghai-like” sublineage spread westwards to the Middle East, Europe, and Africa, and was split up into three different subclusters.^34–36 All Asian cases reported in felids were caused by infections with clade 1 viruses; however, an outbreak in domestic cats in Iraq in February 2006 and the feline cases in Germany were caused by Qinghai-like clade 2 viruses (“EMA” clade 2). Therefore cats seem to be susceptible to different circulating H5N1 virus strains.^34,35

Prevalence of infection in field cats is more or less unknown. One study in Germany showed that prevalence probably is low among pet cats at least in European countries, as neither virus excretion nor antibodies were detected in 171 cats with outdoor access in areas in which infected birds had been found at the time of investigation.³⁷ Also, an epidemiological study in Italy testing cats from Milan did not find any evidence of antibodies to influenza A viruses, either to subtype H5N1 or to other subtypes.³⁸ However, no outbreaks of avian influenza had occurred in this sampling area in Italy and thus likelihood of finding cats with antibodies there was extremely low. In contrast, 7 per cent of field cats (8/111) tested in an unpublished study of the National Institute of Animal Health in Bangkok and 20 per cent of 500 cats tested in Indonesia (unpublished study by Nidom) had antibodies to influenza A H5N1. Because the results of these Asian studies have not been evaluated scientifically and there is no reference to the applied methods, it is possible that the numbers are falsely high. It also is possible that the virus strains circulating in Asia have a higher pathogenicity in cats than the European lineage, and thus more cats were infected. Most likely, however, the difference in prevalence among cats is caused by higher risk of exposure to the virus and higher infection pressure in Asia. In contrast to the situation in Asia, only single wild birds and just a few poultry farms were affected in Europe. Additionally, cats included in the European studies were pet cats, which were fed by their owners and thus did not rely on hunting birds.

PATHOGENESIS

After transmission, the virus spreads directly to the lower respiratory tract, where it can cause severe pneumonia.^1,2,6 Predominant involvement of the lower respiratory tract and inability of the virus to attach to cells of the upper respiratory tract may be a reason why cats excrete virus at relatively low concentrations.^4,39

Unlike other influenza viruses, which usually are restricted to the respiratory tract in mammals, HPAIV H5N1 not only replicates in respiratory tissue but also can lead to systemic infection causing severe necrosis and inflammation in many organs.⁴⁰ Two ways of virus spread to extrarespiratory tissue are discussed. The pattern of virus distribution in the body makes virus entry via viremia very likely. Alternatively, virus may enter from the intestinal lumen via nerve fibers into intestinal tissue; this hypothesis is supported by the finding of ganglioneuritis of the intestinal nervous plexi in cats who had been fed on virus-infected chicken.⁴⁰

TRANSMISSION

Virus transmission occurs mostly through direct contact of felids with infected birds, particularly through eating infected raw poultry.^1,2,4 Both inhalation and ingestion seem to be potential routes of virus entry.^35,40 In addition, indirect virus transmission may occur after contact with contaminated bird feces; this was the suspected mode of transmission in the infected cats in Graz, Austria.³ After experimental infection, horizontal transmission to other cats through direct contact is possible.⁴ Most likely, horizontal transmission also occurred under natural circumstances in the outbreak in the Sriracha tiger zoo.⁵

Infected felids excrete virus via the respiratory, digestive, and urinary tracts, as demonstrated through virus detection in pharyngeal, nasal, and rectal swabs as well as urine and fecal samples.^2,6,35,40 Virus shedding may occur before the onset of clinical signs.^40,41 In an experimental study, virus excretion started at day 3 after infection and lasted until day 7, when the animals were euthanized.^4,40 Subclinically infected cats are assumed to excrete virus less than 2 weeks after infection.³ So far, no case of virus transmission from cats to other species, including human beings, has been observed. Experimentally infected cats did not transmit to dogs in contact, and experimentally infected dogs did not transmit to cats.²³